Synthesis and Evaluation of Linear and Macrocyclic Dolastatin 10 Analogues Containing Pyrrolidine Ring Modifications

ACS Omega
Michinori AkaiwaBrian A Mendelsohn

Abstract

Because of their potent cytotoxic activity, members of the auristatin family (synthetic analogues of the naturally occurring dolastatin 10) have remained a target of significant research, most notably in the context of antibody drug conjugate payloads. Typically, modifications of the backbone scaffold of dolastatin 10 have focused on variations of the N-terminal (P1) and C-terminal (P5) subunits. Scant attention has been paid thus far to the P4 subunit in the scientific literature. In this paper, we introduce an azide functional group at the P4 subunit, resulting in potent cytotoxic activity seen in vitro. Another highly active compound in this study contained azide functional groups in both the P2 and P4 subunits and required dolavaline as the P1 subunit and a phenylalanine as the P5 subunit. Furthermore, these two azide groups served not only as modifiers of cytotoxicity but also as handles for linker attachment or as a tether for use in the synthesis of a macrocyclic analogue.

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Citations

Aug 1, 2019·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Min-Ho ParkYoung G Shin
Mar 3, 2020·Chemical & Pharmaceutical Bulletin·Michinori AkaiwaBrian A Mendelsohn
Mar 11, 2020·Pharmaceuticals·Danah Al ShaerBeatriz G de la Torre
Jan 15, 2020·Current Medicinal Chemistry·Dario MatuljaDean Marković
Aug 23, 2020·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Filip BorysHanna Fabczak
May 18, 2020·European Journal of Cell Biology·Vladimír ČermákJan Brábek

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Methods Mentioned

BETA
NMR
column chromatography

Software Mentioned

ACD
PhysChem Batch

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